Myeloproliferative disorders (MPDs), or neoplasms (MPNs), are a group of conditions generally characterized by chronic increases in some or all of the blood cells (platelets, white blood cells, and red blood cells) [Talarico et al. (1998) Patient Care 30:37-57; Yavorkovsky et al. (2001) J Clin Oncol 19:3790-3792; and Campbell et at (2006) N Engl J Med 355:2452-2-466]. This group of blood disorders includes polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (e.g., primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis), and chronic myeloid leukemia (CML). PV is characterized by increased production of all 3 types of blood cells, whereas ET is manifest in the elevation of platelets. Myelofibrosis (MF) is a disease in which fibrous (scar-like) tissues develop in the bone marrow as a result of abnormal production of red cells, white cells, and/or platelets. CML is characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the peripheral blood.
It is generally thought that MPDs arise from a transformation in a hematopoietic stem cell. Indeed, CML is now defined by its causative molecular lesion, the BCR-ABL fusion gene, which most commonly results from the Philadelphia translocation (Ph). Accordingly, CML is characterized as a BCR-ABL positive (+) myeloproliferative disorder. Discovery of this defined molecular defect lead to the development of the drug imatinib mesylate (Gleevec; Novartis, Basel, Switzerland) to treat CML [Druker et al. (2001) N Engl J Med 344:1031-1037].
The other three myeloproliferative neoplasms (PV, ET, and MF) are characterized as BCR-ABL-negative myeloproliferative disorder. Recently, several groups identified a gain-of-function mutation of tyrosine kinase JAK2 (JAK2V617F) as a major molecular defect in approximately 90% patients with PV, approximately 50% of patients with ET, and approximately 50-60% of patients with MF [Baxter et al. (2005) Lancet 365:1054-1061; James et al (2005) Nature 434:1144-1148; Kralovics (2005) N. Engl. J. Med. 352:1770-1790]. Interestingly, recent studies have demonstrated that nearly 1% of blood samples collected from hospital patients test positive for the JAK2V617F mutation [Xu et al. (2007) Blood 109:339-342]. Most of these JAKV617F-positive patients do not meet the criteria for diagnosis of MPDs but developed vascular diseases, including thrombosis, coronary heart disease, arteriosclerosis, cerebral ischemia, and cerebral infarction at a higher rate than JAKV617F-negative patients. These data suggest that MPDs and pre-MPDs conditions may represent a more profound public health problem than originally anticipated and further emphasizes the pathologic importance of the JAK2V617F as well as other Janus kinase mutations.
Allogeneic hematopoietic stem cell transplantation is the only known cure for BCR-ABL-negative MPDs [Gupta et al. (2012) Blood 120:1367-1379]. However, stem cell treatment-related mortality is high and only a minority of patients qualify for transplantation. While the development and use of JAK inhibitors represents a significant therapeutic advancement, there are clear limitations to their use in the treatment of BCR-ABL-negative MPDs. In particular, JAK inhibitors appear to be useful for reducing splenomegaly in myelofibrosis patients; however, their effects on the disease are otherwise largely palliative [Gupta et al. (2012) Blood 120:1367-1379]. In particular, JAK inhibitors have little to no effect on many manifestations (complications) of the disease including, for example, cytopenia, transfusion dependence, accelerated or blast phase disease, and fibrosis. Moreover, JAK inhibitors have been shown to promote or worsen thrombocytopenia, anemia, and neutropenia in some patients.
Thus, there is a high, unmet need for effective therapies treating MPDs and Janus kinase-associated disorders. Accordingly, it is an object of the present disclosure to provide methods for treating, preventing, or reducing the progression rate and/or severity of MPDs or Janus kinase-associated disorders or one or more complications of MPDs or Janus kinase-associated disorders.